Nutrition-enhancing feed additives are an essential component of animal nutrition today. They are used to improve the utilization of the nutrient supply, stimulate growth and promote protein formation. One of the most important of these additives is the essential amino acid methionine, which occupies a prominent position as a feed additive particularly in poultry rearing. In this field, however, so-called methionine substitutes or methionine hydroxy analogue, (abbreviated to MHA) are gaining increasing importance, since they exhibit growth-stimulating properties similar to those of the amino acid known for this purpose.
The racemic form of 2-hydroxy-4-methylthiobutyric acid is a methionine substitute that has been known for a long time, which is used mainly in animal nutrition, particularly in the rearing of poultry, as a feed additive. This MHA is used instead of methionine and improves the utilization of protein in the feed. In addition, in the form of its calcium salt, it is also used pharmaceutically in the treatment of renal insufficiency.
The industrial production of the above-mentioned MHA typically takes place by reaction of 3-methylthio-propionaldehyde with hydrogen cyanide to form 2-hydroxy-4-methylthiobutyronitrile (MMP cyanohydrin), which is then hydrolyzed in two steps to form MHA. A two-step hydrolysis of the nitrile with stoichiometric quantities of strong mineral acids, such as sulfuric acid, via the step of the carboxamide, to form MHA and the ammonium salt of the mineral acid is described in numerous patents (e.g. EP 0 143 100). In complex extractions with organic solvents and backwash of the MHA into an aqueous phase, the product is separated from the mineral acid, which is used in excess, and its ammonium salt. Inorganic waste products form in considerable quantities in this process.
As an alternative to the acid hydrolysis, enzymatic processes have been described. In WO 96/09403, a nitrilase is described which can hydrolyze the two enantiomers of MMP cyanohydrin to form racemic MHA ammonium salt. However, the enzymes are obtainable only with difficulty and their recovery from the reaction solution is very complex. The problem of recovering the enzyme is solved in WO 02/00869 by the use of water-insoluble, enzyme-containing granules. However, the production of the enzyme-containing granules is difficult, and the half-life of the enzyme activity is given in ranges of up to 70 hours. A significantly longer-lasting activity is expected of a catalyst in an economic process.
In another synthesis strategy, the nitrile is hydrolyzed to the amide in a first step and then the amide is further hydrolyzed to the ammonium salt of MHA. WO 02/070717 discloses a nitrile hydratase, which specifically saponifies MMP cyanohydrin to MHA amide. The hydrolysis of cyanohydrin with the aid of a heterogeneous catalyst is also known. The production of the corresponding acid amide from acetone cyanohydrin with manganese dioxide and an oxidizing agent is disclosed in the patent EP 0 433 611. In the Japanese published patent application Hei 10-128113 from 1998, the production of a catalytically active manganese oxide is claimed, which catalyses the reaction of MMP cyanohydrin to the amide with very high selectivity. However, it is also possible to isolate the amide in a sulfuric acid hydrolysis of the cyanohydrin. WO 01/60789 shows that the methionine amide and its hydroxy analogue can be hydrolyzed with titanium-containing catalysts to form the ammonium salt of methionine or MHA. Here, however, there is the disadvantage of a two-step reaction with two different catalysts and an isolation of the intermediate.
The main commercial form of MHA is a highly concentrated aqueous solution. During storage, an equilibrium forms from the monomeric compound with the di-, tri- and oligomeric MHA. Its effectiveness as a feed additive, compared with methionine, is further reduced by the proportion of the higher molecular weight compounds. It is known that salts of MHA in solid and dissolved form are stable and no higher molecular weight compounds form.